Dermal delivery device

ABSTRACT

A transdermal drug delivery device is disclosed. Over an extended wear period, the device causes cumulative moderate irritation plus significant irritation of less than 5% and/or achieves a meaningful degree of detachment over a seven day period of less than 20%.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. Application Ser. No.PCT/US2008/069618, filed Jul. 10, 2008, which claims benefit of U.S.Provisional Application 60/948,757, filed Jul. 10, 2007, and also acontinuation-in-part of U.S. Application Ser. No. PCT/US2008/069622,filed Jul. 10, 2008, which claims benefit of U.S. ProvisionalApplication 60/948,759, filed Jul. 10, 2007, the entire contents of allof the preceding being incorporated by reference herein.

FIELD OF THE INVENTION

This invention is in the field of delivery of pharmacologically orcosmetically active agents to the skin for systemic, local, or topicaladministration.

BACKGROUND OF THE INVENTION

A dermal delivery device is an adhesive “patch” for application to theskin that is used to deliver a wide variety of pharmacologically andcosmetically active agents. Such patches can be used to deliver an agenttransdermally, i.e., through the skin and into the bloodstream forsystemic treatment or into or through the skin for local treatment. Suchpatches can also be used to administer topical treatments, includingcosmetically active agents.

Transdermal drug delivery devices intended for extended wear, i.e., 3 ormore days, are susceptible to problems of inadequate adhesion and/orskin irritation. Irritation can be caused or exacerbated by a number offactors, including the nature of the active. Certain skin permeationenhancers are also known to contribute to irritation. These includedimethyl sulfoxide (DMSO) and long chain aliphatic compounds includingfatty acids, such as laurates and oleates and derivatives thereof, e.g.,lauryl alcohol.

Various attempts have been made to address the skin irritation problem.These include controlling the rate of transdermal delivery of irritatingdrugs through use of a rate controlling membrane, inclusion ofirritation inhibitors such as a lysozymal uptake inhibitor, a complexingagent, a second active agent that reduces irritation/sensitization, asucrose fatty acid, aluminum hydroxide and/or titanium oxide. In somecases, a particular salt of an irritating active may be found to be lessirritating.

SUMMARY OF THE INVENTION

This invention relates to extended wear dermal delivery devices, orpatches, that cause cumulative moderate irritation plus significantirritation of less than 5%.

This invention also relates to extended wear dermal delivery devices, orpatches, that achieve a meaningful degree of detachment of less than20%.

In illustrative embodiments, the device of the invention, over a sevenday wear period, causes cumulative moderate irritation plus significantirritation of less than 5% and additionally achieves a meaningful degreeof detachment over a seven day period of less than 20%.

Thus, in general terms, the inventions relates to a transdermal drugdelivery patch comprising (A) an active ingredient (AI) layer having askin contacting surface and a non-skin contacting surface and comprisinga pressure sensitive adhesive and the drug and (B) an elastic and porousbacking material whereby at the end of an extended wear period, thepatch causes cumulative moderate irritation plus significant irritationof less than 5% or causes cumulative moderate irritation plussignificant irritation of less than 5% and a meaningful degree ofdetachment over a seven day period of less than 20%, or both.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an exploded cross-section of an illustrative dermaldelivery system of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have discovered that skin irritation, which can be aproblem with extended wear patches (e.g., 3 or more days), can beminimized, and adhesion can be enhanced, by careful patch design andformulation. Through such design, use of a rate controlling membrane isunnecessary, particularly when the AI layer comprises a polymeric matrixcomprising a PSA, e.g., as described below. It may also not be necessaryto employ irritation inhibitors or to employ particular salt formsselected on the basis of reduced irritancy.

It may also be possible to employ skin permeation enhancers that areknown to be skin irritants because removal of other sources ofirritation, e.g., physical stress on the skin, are minimized. Suchpermeation enhancers include, e.g., dimethyl sulfoxide (DMSO) and longchain aliphatic compounds such as fatty acids or esters or derivative offatty acids, e.g., C₈-C₂₀ saturated or unsaturated fatty acids such aslauryl lactate and isopropyl myristate. These include, e.g., C₈-C₂₀saturated or unsaturated fatty alcohols, such as myristyl, palmityl oroleyl alcohols.

Thus, in illustrative embodiments of the invention, patches do notcomprise a skin irritation inhibitor, do not employ a rate-controllingmembrane, do not employ a non-irritating salt of an irritating active,and/or do not require a supporting layer for the AI layer that isflexible and porous. It is also not necessary to employ an adhesionadjusting agent, such as polydiorganosiloxane polymer in order to reducetissue damage upon removal of the patch.

In an illustrative embodiment of the invention, the patch is intendedfor application to normal healthy skin, such as on the arm, chest, back,buttocks or leg, although other embodiments can be designed for use oninflamed or irritated skin tissue. In illustrative embodiments, therelease and transdermal administration are dependent on drugconcentration in the AI layer.

For example, designing and formulating a patch that adheres well canreduce irritation from physical stresses on the skin such as byminimizing friction caused by movement of the patch against the skin;use of materials that are elastic such that they conform by stretchingand re-forming (i.e., recovering more or less its original dimensionsafter being stretched during wear) can improve adhesion and minimizeirritation by improving adhesion and/or by minimizing the frictionbetween the patch and the skin; use of materials that are soft such thatthey do not have “hard” edges can minimize irritation such as byreducing friction between the edges of the patch or of its components,e.g., an overlay, and the skin; use of a humectant such as PVP canimprove adhesion and reduce irritation such as by minimizing buildup ofmoisture between the patch or its components and the skin; use of abacking material that is porous (i.e., water vapor-permeable to theextent that moisture that does build up in the AI layer or in theextended perimeter of an overlay can escape) can improve adhesion bypreventing buildup of moisture and also thereby reduce irritation.

A covering that is attached directly or indirectly to the AI layer,e.g., an overlay can comprise an elastic and porous material adjacentthe non-skin-contacting surface of the AI layer. By “elastic” is meantthat the material is capable of stretching with skin movement duringnormal activities and of re-forming substantially to its original shapeand size. By “porous” is meant that the material is permeable, i.e.,permeable to moisture, more specifically, permeable to water vapor. Theelasticity and porosity of such backing material are such that, at theend of an extended, e.g., seven day, wear period, the patch causescumulative moderate irritation plus significant irritation of less than5%, including 4% or less, 3% or less, and 2% or less and/or such thatthere is a meaningful degree of detachment over a seven day period ofless than 20%.

Preferably, such elastomeric and permeable layer is part of an overlaythat extends beyond the perimeter of the AI layer. In this case, aninternal backing layer that comprises a non-porous material covering allor a portion of the non-skin contacting surface of the active ingredientlayer can be used to prevent or minimize passage of the components ofthe polymer matrix in the AI layer through the non-skin-contactingsurface of the device. In this embodiment, the elastic and porousbacking material in the overlay provides sufficient elasticity andpermeability to the device to confer adequate adhesion and acceptableirritation, i.e., moderate irritation plus significant irritation of <5%including 4% or less, 3% or less, and 2% or less.

In a particular illustrative embodiment, an impermeable internal backinglayer is adhered to the entire surface area of the non-skin contactingface of the active ingredient layer. In such embodiment, a peripheraladhesive system such as an overlay is employed to improve adhesion andreduce irritation, particularly by proper choice of a PSA and overlaymaterial. Polyisobutylene (PIB) PSAs, such as are described below, areparticularly useful in the PSA layer of the overlay. Other usefulmaterials for the overlay include materials that are flexible, includingmultidimensionally elastically stretchable films or fabrics. Suchelastomeric and soft materials include porous foams and woven ornonwoven fabrics, which will stretch and reform with movement of theskin, retain their shape and reduce buildup of moisture between theperipheral adhesive layer and the skin. The porosity of the material canbe chosen such that the water vapor permeation rate through the materialis higher than the transepidermal water loss.

When PSAs that are of low molecular weight such that they would passthrough the permeable, i.e., porous, overlay covering, e.g., a PIB, areemployed in the overlay, it can be useful also to employ an intermediatelayer that permits moisture, but not the PSA, to reach and penetrate theporous material. Such intermediate layer, which need not detract fromthe elasticity of the backing layer, can be, e.g., a polyacrylate PSA ora polyurethane. In addition, if the PSA is hydrophobic, such as a PIBPSA, it is advantageous to employ a humectant, such as PVP, in the PSAlayer of the overlay.

As noted above and discussed below, the overlay can extend beyond theperimeter of the AI layer in all directions, typically by a margin ofabout 0.1 to about 1.5 cm, more specifically about 0.3 to about 1.2 cmand more specifically about 0.8 cm beyond the perimeter of the AI layer.The precise surface area of extension is selected to provide aperipheral adhesive surface area that is adequate to ensure goodadhesion throughout the contemplated wear period but that is not largerthan necessary. Use of an overlay that is larger than necessary hasseveral disadvantages, e.g., a larger skin contact surface area canincrease irritation and is generally more noticeable and therefore lessaesthetically pleasing; in some embodiments, a patch surface area,including a peripheral adhesive, can be less than about 50 cm², lessthan about 30 cm², or less than about 25 cm².

Such patch design also preferably incorporates a humectant into thepolymeric matrix of the AI layer. As mentioned above and furtherdescribed below, the humectant absorbs moisture from the surface of theskin and thereby reduces irritation and enhances adhesion.

Patches designed as described above and as illustrated hereinbelow, atthe end of an extended, e.g., seven day, wear period, can causecumulative moderate irritation plus significant irritation of less than5%, including 4% or less, 3% or less, and 2% and/or can achieve ameaningful degree of detachment over a seven day period of less than20%, including less than 18%, less than 15%, less than 12%, and lessthan 10%.

By “moderate irritation plus significant irritation” is meant that thepatch causes erythema, papules, definite edema, vesicular eruption, withthe reaction spreading beyond test (i.e., application) site. Withreference to the FDA's draft Guidance on Ethinyl Estradiol;Norelgestromin extended release/transdermal film, July 2009 (“FDAGuidance”), a copy of which is incorporated herein as though fully setforth, “moderate irritation plus significant irritation” corresponds toa Dermal Response/Skin Appearance score of 7.

A cumulative moderate irritation plus significant irritation of lessthan 5% means that moderate irritation plus significant irritation wasobserved in fewer than 5% of skin application sites on patients in astudy population of, e.g., about 50 to about 1000 patients, e.g., about100 to about 300 patients, including 200 patients which is the number ofpatients recommended in the FDA Guidance.

By “meaningful degree of detachment” is meant that a patch is less than50% adhered, i.e., more than half of the patch has become detached fromthe skin. With reference to the FDA Guidance, “meaningful degree ofdetachment” corresponds to an Adhesion score of 3 or 4.

A meaningful degree of detachment over a seven day period of less than20%, means that there was a meaningful degree of detachment in fewerthan 20% of patients in a study population of, e.g., 10 to 1000patients.

A mean adhesion score means the mean (p<0.05) adhesion score in apopulation of patients (n=100 to 500) using the following adhesionscoring patch:

-   0=>/=90% adhered (essentially no lift off the skin)-   1=>/=75% to <90% adhered (some edges only lifting off the skin)-   2=>/=50% to 75% adhered (less than half of the patch lifting off the    skin)-   3=>0% to <50% adhered but not detached (more than half of the patch    lifting off the skin without falling off)-   4=0% adhered—patch detached (patch completely off the skin).

In illustrative embodiments of the invention, the patch achieves both, acumulative moderate irritation plus significant irritation of less than5% and a meaningful degree of detachment over a seven day period of lessthan 20%.

In certain illustrative embodiments, the overlay can be packagedseparately from the AI layer. An internal backing layer can beintegrated with the AI layer or with the overlay. In either case, theuser would apply the overlay on top of the AI layer, rather thanapplying an integrated patch that comprises both the overlay and the AIlayer.

The description that follows is of an illustrative embodiment of theinvention for dermal delivery of a composition comprising contraceptivehormones and that comprises one or more volatile components. Of course,the active can be any drug that is active when administered bytransdermal delivery, passive or otherwise. Furthermore, while use of aseal between an overlay and a release liner to minimize or prevent lossof volatile components, as described hereinbelow, can be advantageous,such seal is not an essential feature of the current invention which ismore broadly directed at achieving adequate adhesion and acceptable skinirritation.

With reference to FIG. 1, this illustrative device of the inventioncomprises 4 layers. One is the AI layer (6). The second is a releaseliner (4). The third is an internal backing layer (5). The fourth is anoverlay, which in this illustrative device, itself comprises threecomponent layers (1,2,3), referred to herein below as, respectively, aPSA layer (3), an intermediate layer (2), and an overlay covering oroverlay coating (1). The overlay can also be described as comprising, inthis illustrative embodiment, a PSA layer (3) and an overlay covering (1and 2). In any event, one feature of this illustrative embodiment of theinvention is formation of a seal between the PSA layer (3) of theoverlay (1,2,3) and the release liner (4).

A feature of a related aspect of this illustrative embodiment of theinvention is use of a PIB PSA in the PSA layer (3) of the overlay(1,2,3).

A feature of another related aspect of this illustrative embodiment ofthe invention is use of an overlay (1,2,3) comprising a PIB PSA layer(3) and a material (1,2) that covers the PIB PSA layer, so that the PIBPSA does not come into contact with fingers or clothing, but thatpermits water vapor transmission outward from the skin. As illustratedin FIG. 1, the material comprises Layers 1 and 2, Layer 2 being a PSAthat prevents migration of the PIB PSA into the overlay coating (1).

A feature of another aspect of this illustrative embodiment of theinvention is use of an intermediate layer (2) between the PIB PSA layer(3) and a porous overlay covering (1).

In illustrative embodiments, the entire patch is flexible so that itwill adhere effectively and comfortably to the contours of the site ofapplication and so that it will withstand the flexions associated withnormal living activities.

These and other aspects of the invention are more fully describedhereinbelow or otherwise will be apparent to a person of ordinary skillin the art based on such description.

An illustrative, non-limiting, embodiment of the invention thatcomprises an entire transdermal delivery system of the invention is asfollows.

The AI Layer

Layer 6 comprises the AI and a volatile component, typically in a PSAmatrix. The volatile component is typically at least partially dissolvedin the AI layer. So, for example, in an illustrative embodiment of theinvention, Layer 6 comprises one or more hormones as AIs, an acrylicPSA, and a volatile skin permeation enhancer. The volatile component,however, can also be, for example, the AI itself or a solvent orcarrier. Illustrative formulations of transdermal hormone compositionsuseful in delivery devices of the present invention are described, forexample, in U.S. Pat. No. 7,045,145 and in US 20070065495.

In an illustrative embodiment, the AI is an active pharmaceuticalingredient (API) that is one or more hormones such as a progestin, e.g.,levonorgestrel, and an estrogen, e.g., ethinyl estradiol or 17-βestradiol, dispersed in an adhesive polymer matrix. In another aspect ofthe invention for delivery of a hormone, the API is limited only to aprogestin. In other such aspects, the API comprises a progestin, anestrogen and a testosterone, or a testosterone alone.

Other APIs that can also be delivered in accordance with this inventioninclude “small molecules”, i.e., low molecular weight (e.g., <2000Daltons) synthetic organic compounds such as but not limited tofentanyl, nicotine, scopolamine, nitroglycerine, clonidine,methylphenidate, lidocaine, prilocaine, oxybutynin, antipsychotics suchas fluphenazine, alprazolam, risperidone, and olanzapine, Parkinsonsdrugs such as rotigotine and selegilene Alzheimer's drugs such asrivastigmine and donepezil, anti-hypertensives such as enalapril, BPHdrugs such as tamsulosin and terazosin, and anti-asthma drugs such asalbuterol and montelukast.

The AI can also be a cosmetic agent such as keratolytic agents such asalpha- and beta-hydroxycarboxylic acids and beta-ketocarboxylic acids;alpha-hydroxy acids such as glycolic acid, lactic acid, tartaric acid,malic acid, citric acid, mandelic acid and, in general, fruit acids;beta-hydroxy acids such as salicylic acid and its derivatives;antibacterials such as clindamicyn or erythromycin phosphate, orantibiotics of the tetracycline type; ascorbic acid and its biologicallycompatible salts and esters; enzymes; tautening agents such as protein,soya and wheat powders; hydroxylated polyacids; sucroses and theirderivatives; urea; amino acids; plant and yeast extracts; proteinhydrolysates such as collagen and elastin hydrolysates; hyaluronic acid;mucopolysaccharides; vitamins; panthenol; folic acid; acetylsalicylicacid; allantoin; kojic acid; hydroquinone; retinoic acid and derivativesthereof; fatty acids; etc.

As described in US 20070065495, an illustrative Layer 6 is prepared asdescribed in Example 1, below. This example describes formulations thatuse a combination of skin permeation enhancers, including DMSO and alower (C1-C4) alkyl ester of lactic acid such as ethyl lactate, both ofwhich are volatile components and are examples of volatile componentsthat may be included in a transdermal drug delivery device of theinvention. By “volatile,” is meant that the agent has a vapor pressureabove 0.1 mm Hg at 20 C. Other illustrative volatile components usefulin the present invention are known to those skilled in the art andinclude other volatile organic solvents, for example, sulfoxides such asdecyl methyl sulfoxide; alcohols such as ethanol, propanols, hexanols,and benzyl alcohol, fatty acids such as valeric acid, isovaleric acid,isopropyl butyrate, ethyl acetate, and butyl acetate; polyols such asbutanediol and ethylene glycol; amides such as dimethylacetamide,diethyl toluamide, dimethylformamide, pyrrolidone, andmethylpyrrolidone; terpenes such as limonene, pinene, terpinone,mentone, eucalyptus, and menthol; alkanes such as hexane and heptane,and organic acids such as citric acid.

Skin permeation enhancers and solvents additional to DMSO and similarorganic solvents include but are not limited to those described inExample 1.

The following description relates to a preferred formulation of Layer 6for delivery of a hormone, said layer, or patch, comprising one or morehormones, skin permeation enhancers, and a PSA matrix comprising anadhesive polymer and a humectant/plasticizer.

Skin Permeation Enhancers: Drug molecules released from a transdermaldelivery system must be capable of penetrating each layer of skin. Inorder to increase the rate of permeation of drug molecules, atransdermal drug delivery system, desirably, is able to increase thepermeability of the outermost layer of skin, the stratum corneum, whichprovides the most resistance to the penetration of molecules. In thisregard, the present invention allows for a transdermal drug deliverysystem that employs one or more skin permeation enhancers in specificamounts.

A combination of skin permeation enhancing agents is preferably employedin the practice of the present invention for delivery of levonorgestreland ethinyl estradiol (EE) or 17 beta-estradiol. The combinationcomprises a mixture of (1) a pharmaceutically acceptable organicsolvent, such as dimethyl sulfoxide (DMSO), (2) a fatty (C8-C20) alcoholester of a hydroxy acid, such as lauryl lactate, (3) a lower (C1-C4)alkyl ester of a hydroxy acid, e.g., ethyl lactate, and (4) a C6-C18fatty acid, such as capric acid. In specific embodiments, the fattyalcohol ester of lactic acid is lauryl lactate and the lower alkyl esterof lactic acid is ethyl lactate. A medium- to long-chain fatty acid inthe skin permeation enhancer formulation can be employed among the skinpermeation enhancers. Capric acid is preferred for use but other C6-C18saturated or unsaturated fatty acids may be used, including but notlimited to caproic acid, caprytic acid, lauric acid and myristic acid,to name a few.

These skin permeation enhancers can be present in amounts as describedbelow. In certain embodiments, one or more of the skin permeationenhancers may be eliminated from the polymer matrix.

In a particular such embodiment, the pharmaceutically acceptable organicsolvent is DMSO. Other organic solvents suitable for use in the presentinvention include, but are not limited to, C1-C8 branched or unbranchedalcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol,and the like, as well as azone (laurocapram:1-dodecylhexahydro-2H-azepin-2-one) and methylsulfonylmethane, to name afew.

The fatty alcohol ester of a hydroxy acid can be a fatty alcohol esterof lactic acid, such as lauryl lactate. However, other hydroxy acids andfatty alcohols may be utilized. Alternative hydroxy acids include, butare not limited to, alpha-hydroxy acids such as glycolic acid, tartaricacid, citric acid, malic acid and mandelic acid, as well as thebeta-hydroxy acid, salicylic acid. Alternative fatty alcohols includeany C8-C20 saturated or unsaturated fatty alcohols, such as myristyl,palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid can also utilize lactic acid, andcan be, e.g., ethyl lactate. However, other hydroxy acids, such asglycolic acid, tartaric acid, citric acid, malic acid, mandelic acid andsalicylic acid, may also be utilized. In addition isopropylmyristic acid(IPM) may be used as a substitute for the lower alkyl ester of hydroxyacid.

The aforementioned combination of skin permeation enhancers may be usedto enhance transdermal delivery of steroid hormones from any type oftransdermal delivery device. An adhesive polymer matrix-type system asdescribed in detail herein is preferred for use; however, the enhancercombination may also be utilized in non-adhesive polymers, as well as inmulti-layer or reservoir-type transdermal delivery systems, to name afew.

Hormones: A transdermal drug delivery device utilizing theaforementioned skin permeation enhancers can be used to deliver varioustypes of API, including a hormone, capable of transdermal delivery. Inone embodiment, a combination of a progestin and an estrogen is utilizedfor one or more of the following purposes: (1) control of fertility, (2)control of acne, (3) treatment of endometriosis, (4) treatment ofpremenstrual dysphoric disorder (PMDD), and (5) induction of amennorhea.In another embodiment, a progestin alone is utilized for one or more ofthe following purposes: (1) control of fertility, (2) supportingpregnancy, (3) as an alternative hormonal therapy for individuals forwhom estrogen is contra-indicated (e.g., lactating females), and (4)preventing galactorrhea. In still another embodiment, a combination ofprogestin, estrogen and testosterone is utilized as a hormonereplacement therapy for the treatment of deficiency of these hormones infemales. Yet another embodiment is directed to a THDS formulated fordelivery of testosterone alone, which is useful for the treatment ofdecreased libido resulting from testosterone deficiency in both malesand females.

Levonorgestrel is a potent progestin on a weight-dose basis, which is animportant factor since the progestins often exhibit a much lesser degreeof transdermal absorption than do the estrogens. Other progestins thatcould be used in part or total are norgestrel, norgestimate,desogestrel, gestodene, norethindrone, nore-thynodrel, hydrogesterone,ethynodiol dicetate, hydroxyprogesterone caproate, medroxyprogesteroneacetate, norethindrone acetate, progesterone, megestrol acetate,gestogen and certain others which are biocompatible and absorbabletransdermally. These include biocompatible derivatives of progestinsthat are transdermally absorbed, some of which, advantageously, arebioconvertible after transdermal absorption to the original progestin.The progestin and other hormones selected preferably have highcompatibility with each other.

For combinations of progestin with estrogen, the synthetic hormoneethinyl estradiol is particularly suitable, although natural estrogen orother analogs can be used. This hormone may be transdermally deliveredin conjunction with the particularly suitable progestin, levonorgestrel,by a TDHS of the present invention at desirable daily rates for bothhormones. Ethinyl estradiol and levonorgestrel are compatible and can bedispersed in the adhesive polymer formulation. Typically, a transdermaldosage unit designed for one-week therapy should deliver at least about20 μg/day of levonorgestrel, e.g., about 50 to about 100 μg/day (or anequivalent effective amount of another progestin) and 10-50 μg/day ofethinyl estradiol (or an equivalent effective amount of anotherestrogen). Those respective amounts of progestin and estrogen arebelieved to be necessary to inhibit ovulation and to maintain normalfemale physiology and characteristics. In the present invention, theamount of levonorgestrel transdermally delivered is preferably 30 μg perday for more than one day to about one week with a 15 cm² transdermaldelivery device.

Derivatives of 17 β-estradiol that are biocompatible, capable of beingabsorbed transdermally and preferably bioconvertible to 17 β-estradiolmay also be used, if the amount of absorption meets the required dailydose of the estrogen component and if the hormone components arecompatible. Such derivatives of estradiol include esters, either mono-or di-esters. The monoesters can be either 3- or 17-esters. Theestradiol esters can be, illustratively speaking,estradiol-3,17-diacetate; estradiol-3-acetate; estradiol 17-acetate;estradiol-3,17-divalerate; estradiol-3-valerate; estradiol-17-valerate;3-mono-, 17-mono- and 3,17-dipivilate esters; 3-mono-, 17-mono- and3,17-dipropionate esters; 3-mono-, 17-mono- and 3,17-dicyclopentyl-propionate esters; corresponding cypionate, heptanoate, benzoateand the like esters; ethinyl estradiol; estrone; and other estrogenicsteroids and derivatives thereof that are transdermally absorbable.

Combinations of the above with estradiol itself (for example, acombination of estradiol and estradiol-17-valerate or further acombination of estradiol-17-valerate and estradiol-3,17-divalerate) canbe used with beneficial results. For example, 15-80% of each compoundbased on the total weight of the estrogenic steroid component can beused to obtain the desired result. Other combinations can also be usedto obtain desired absorption and levels of 17 β-estradiol in the body ofthe subject being treated.

Formulations comprising testosterone may utilize natural testosterone orsynthetic testosterones that are absorbed transdermally. For instance,methyl testosterone is suitable for use in the present invention. Atransdermal device for testosterone delivery in premenopausal womenshould be formulated for delivery of up to about 300 ug daily. Fortreatment of testosterone deficiency in males, transdermal hormonedelivery systems should be formulated to deliver up to about 3-6 mgdaily.

It will be appreciated that the hormones may be employed not only in theform of the pure chemical compounds, but also in a mixture with otherpharmaceuticals that may be transdermally applied or with otheringredients which are not incompatible with the desired objective aslisted above. Thus, simple pharmacologically acceptable derivatives ofthe hormones such as ethers, esters, amides, acetals, salts and thelike, if appropriate, may be used. In some cases, such derivatives maybe preferred. The progestin compound and the estrogenic steroid areordinarily dispersed or dissolved concurrently in fabricating thehormone-containing adhesive polymer matrix or they may be dispersed ordissolved separately.

As noted above, this invention is not limited to transdermal delivery ofan estrogen or a progestin or even to transdermal delivery of asteroidal hormone. Instead, the invention can be practiced using a widerange of actives.

Polymers Used as Active Patch Components: The AI-containing layer can bea polymer matrix comprising the pharmaceutically or cosmetically activeingredient. The polymer can be a PSA to form a biologically acceptableadhesive polymer matrix, preferably capable of forming thin films orcoatings through which the AI can pass at a controlled rate. Suitablepolymers are biologically and pharmaceutically compatible,nonallergenic, insoluble in and compatible with body fluids or tissueswith which the device is contacted. The use of water soluble polymers isgenerally less preferred since dissolution or erosion of the matrixwould affect the release rate of the AI as well as the capability of thedosage unit to remain in place on the skin. So, in certain embodiments,the polymer is non-water soluble.

Preferably, polymers used to form a polymer matrix in the AI-containinglayer have glass transition temperatures below room temperature. Thepolymers are preferably non-crystalline but may have some crystallinityif necessary for the development of other desired properties.Cross-linking monomeric units or sites can be incorporated into suchpolymers. For example, cross-linking monomers that can be incorporatedinto polyacrylate polymers include polymethacrylic esters of polyolssuch as butylene diacrylate and dimethacrylate, trimethylol propanetrimethacrylate and the like. Other monomers that provide such sitesinclude allyl acrylate, allyl methacrylate, diallyl maleate and thelike.

A useful adhesive polymer formulation comprises a polyacrylate adhesivepolymer of the general formula (I):

wherein X represents the number of repeating units sufficient to providethe desired properties in the adhesive polymer and R is H or a lower(C1-C10) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyl and thelike. More specifically, it is preferred that the adhesive polymermatrix comprises a polyacrylate adhesive copolymer having a 2-ethylhexylacrylate monomer and approximately 50-60% w/w of vinyl acetate as aco-monomer. An example of a suitable polyacrylate adhesive copolymer foruse in the present invention includes, but is not limited to, that soldunder the tradename of Duro Tak® 87-4098 by National Starch and ChemicalCo., Bridgewater, N.J., which comprises a certain percentage of vinylacetate co-monomer.

Humectant/plasticizer: Preferably, a plasticizer/humectant is dispersedwithin the adhesive polymer formulation. Incorporation of a humectant inthe formulation allows the dosage unit to absorb moisture from thesurface of skin which in turn helps to reduce skin irritation and toprevent the adhesive polymer matrix of the delivery system from failing.The plasticizer/humectant may be a conventional plasticizer used in thepharmaceutical industry, for example, polyvinyl pyrrolidone (PVP). Inparticular, PVP/vinyl acetate (PVPNA) co-polymers, such as those havinga molecular weight of from about 50,000, are suitable for use in thepresent invention. The PVPNA acts as both a plasticizer, acting, tocontrol the rigidity of the polymer matrix, as well as a humectant,acting to regulate moisture content of the matrix. The PVP/VA can be,for example, PVPNA S-630 which is a 60:40 PVP:VA co-polymer that has amolecular weight of 51,000 and a glass transition temperature of 110 C.The amount of humectant/plasticizer is directly related to the durationof adhesion of the overlay. Preferably, the PVP/vinyl acetate is PVP/VAS-630 supplied by International Specialty Products, Inc. (ISP) of Wayne,N.J., wherein the PVP and the vinyl acetate are each present inapproximately equal weight percent.

The shape of the device of the invention is not critical. For example,it can be circular, i.e., a disc, or it can be polygonal, e.g.,rectangular, or elliptical. The surface area of the AI layer generallyshould not exceed about 60 cm² in area. Preferably, it will be about 5to 50 cm², more preferably, about 8 to about 40 cm². Most preferably,the discs will be about 10 to about 20 cm². A disc of 15 cm² ispreferred because of its relatively small size, yet being capable ofdispersing high levels of hormones. Specific embodiments of theinvention feature patches having an AI layer with a surface area of 10,12.5, 15, 17.5 or 20 cm². However, other sizes may be utilized.

In illustrative embodiments, the AI layer is disposed directly betweenthe internal backing layer and the release liner. There is not a“reservoir” or pre-formed pocket, as such; rather, the AI layer andinternal backing layer are hermetically sealed between the overlay andthe release liner.

With such polymeric matrix, the active ingredient does not need to becontained, e.g., in microcapsules or other containment/release means.

The Internal Backing Layer

When the PSA comprises a polyacrylate matrix, as described above, theorganic component can escape through the skin and non-skin contactingsurface of the system. In order to minimize such escape through non-skincontacting surface, an internal backing layer can be employed. Thislayer, which inhibits absorption of components of the AI layer into theoverlay, is illustrated as Layer 5 in FIG. 1.

Such internal backing layer can be made of any suitable material that isimpermeable or substantially impermeable to the AI and to excipients ofthe adhesive polymer matrix. The internal backing layer serves as aprotective cover for the AI layer and provides a support function. Thebacking layer can be formed so that it is essentially the same size asthe hormone-containing adhesive polymer matrix or it can be of largerdimension so that it can extend beyond the edges of the AI-containingpatch outwardly. The backing layer can be any appropriate thickness thatwill provide the desired protective and support functions. A suitablethickness is from about 10 to about 300 microns. More specifically, thethickness is less than about 150 microns, yet more specifically, it isless than about 100 microns, and most specifically, the thickness isless than about 50 microns.

Examples of materials suitable for making the internal backing layer arefilms of polypropylene, polyesters such as poly(ethylene terephthalate),metal foils, metal foil laminates of such suitable polymer films, andthe like. Polyester films, such as Mylar® (DuPont Teijin) and Scotchpak®9732 (3M Company), are particularly suitable for use in the presentinvention.

The internal backing layer is, in general, a separate layer from theoverlay or any component layer of the overlay, e.g., it is notco-extruded or co-molded with the overlay. In illustrative embodiments,the internal backing layer can be coated on the surface adjacent the AIlayer with a “tie-coat,” e.g., a polyvinyl acetate-polyethylene vinylacetate copolymer or other soft polymer or copolymer.

The Release Liner

The surface area of the release liner is greater than that of the AIlayer. This can be seen in FIG. 1, where the diameter (in the case of around device) or width and length (in the case of a polygonal device) ofLayer 3 is greater than that of Layers 5 and 6, such that it extendsbeyond the AI layer in some or all directions.

The release liner is made of any material (1) that is impermeable orsubstantially impermeable to the components of the AI layer, (2) towhich the PSA in the overlay will adhere, as discussed furtherhereinbelow, and (3) that is readily removable by peeling from the AIlayer and overlay PSA just prior to applying to the skin. “Impermeable”and “substantially impermeable,” will be understood to mean that thecomponents of the AI layer, in particular, the volatile components, donot become absorbed by or otherwise pass into or through the releaseliner such as to alter the performance of the device, in particular, theskin permeability or efficacy of the active ingredients.

The release liner can have the same dimensions as the overlay, discussedbelow, or it can extend totally or partially beyond the edge of thepatch. In one illustrative embodiment, the release liner extendspartially beyond the overlay so as to form “tabs” of release linermaterial that extend beyond the edges of the overlay for easy separationof the release liner from the rest of the system.

Preferably, it comprises a fluorinated or siliconized polyester film oranother fluorinated or siliconized polymer such as a polyacrylonitrilecopolymer, or a foil lined with a siliconized or fluorinated polymer.The release liner is preferably not polystyrene because it has beenshown that polystyrene will absorb DMSO. A preferred material for therelease liner when the layer 4 a of the overlay comprises a PTB PSA is aScotchpak® liner (3M Company), such as Scotchpak® 1022 or Scotchpak®9744 fluorinated polyester release liners.

In this illustrative embodiment, a drug-permeable membrane, rate-controlmembrane, porous membrane, seal peel, peelable disk or other layer,covering or coating between the polymeric matrix and the release lineris not required. Instead, in illustrative embodiments, owing to theviscosity of the polymeric matrix, the release liner is in directcontact with the AI layer and, outside the perimeter of the AI layer,with the overlay.

The Overlay

The overlay in this illustrative embodiment comprises three componentlayers, referred to in FIG. 1 as layers 1, 2, and 3. The overlaycomprises a PSA in which the solubility of the volatile components isless, preferably significantly less, than the solubility of those samecomponents in the AI matrix. So, e.g., when the volatile component isDMSO or ethyl lactate, a PIB PSA may be chosen. With reference to FIG.1, the PIB PSA layer is Layer 3. Generally, such FIB PSA comprises a mixof a low to medium molecular weight and a high molecular weight PIB, aplasticizer such as polybutene, and a hydrocolloid such as across-linked polyvinylpyrrolidine. Useful PIBs include, e.g., Oppanol®PIBs (BASF), which have average molecular weights of between 40,000 and4,000,000.

A useful PIB PSA comprises crospovidone such as Kollidon® CLMcrospovidone (BASF) (e.g., 5-45 wt %, preferably 15-30 wt %, and morepreferably 20-25 wt %); a low viscosity PIB such as Oppanol® B12(molecular weight: 51000, viscosity at 150 C: 150 Pascal-seconds) (e.g.,10-60 wt %, preferably 30-50 wt %); a high viscosity PIB such asOppanol® B100 (viscosity: approximately 1100 Pascal-seconds) (e.g., 2-15wt %, preferably 5-15 wt %); a polybutene such as Indopol® 1900(Innovene LLC) (molecular weight: 2500, viscosity at 100 C: 3900-4200centistokes) (e.g., 10-60 wt %, preferably 20-40 wt %); and a mineraloil (0-20 wt %). For example, an illustrative formulation comprisesabout 20 wt % crospovidone, about 40 wt % of a low viscosity PIB, about8 wt % of a high viscosity PIB and about 32 wt % of polybutene. (Theterm, “about,” as used in this specification, means plus or minus 10%.By “low viscosity” is meant less than about 300 Pascal-seconds and by“high viscosity” is meant more than about 800 Pascal-seconds, when theviscosity is measured at 150 C.) Cross-linking of the PVP is usefulbecause such cross-linked polymers tend to be water-swellable but waterinsoluble. Such PIB PSA can provide good wear stability, e.g.,attachment under normal living conditions for at least 7 days.

Other rubber-based polymers that can be used in place of PIB PSA in theoverlay include silicone-based PSAs, such as BIO-PSA® (Dow Corning);copolymers and terpolymers of styrene/butadiene/styrene,styrene/isoprene/styrene, and styrene-ethylene/butylenes-styrene, suchas Kraton D styrene/butadiene and Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styrene.Isoprene rubbers, such as Kraton IR linear polyisoprene homopolymers,can also be used.

As shown in FIG. 1, and like the release liner, the overlay can extendbeyond the perimeter of the AI layer in all directions, typically by amargin of about 0.1 to about 1.5 cm, more specifically about 0.3 toabout 1.2 cm, and yet more specifically about 0.8 cm beyond theperimeter of the AI layer.

The overlay, if it comprises a PSA layer, improves adherence to the skinby supplementing the adhesion provided by the PSA in the AI layer, ifpresent, or, in the case of an AI layer that does not comprise a PSA, itprovides adherence to the skin.

In addition, in one illustrative embodiment of the invention, theoverlay adheres to the release liner around the perimeter of bothlayers, thereby sealing in the components of the AI layer. By properlyselecting the materials that comprise the overlay and the release liner,this seal between them prevents, or substantially prevents, escape ofthe volatile component in the AI layer but still allows the releaseliner to be peeled away easily by the user prior to topical application.

The seal is formed in situ by mechanically pressing together the edgesof the overlay that extend beyond the perimeter of the AI layer and theedges of the release liner that extend beyond the perimeter of the AIlayer. When the first overlay layer is a PIB PSA and the release lineris a fluorinated or siliconized polyester film, a suitable seal can bemade by applying pressure. The amount of pressure required to form suchseal is not critical. Finger pressure is adequate. Of course, in anillustrative embodiment of the invention, it is desirable that the sealcan be broken by peeling the release liner from the rest of the systemby hand just prior to application to the skin.

The seal between the overlay PSA and the release liner prevents, orsubstantially prevents, loss of the components of the AI layer throughthe seal between these two layers such as during storage of the system.

The seal can also be formed by ultrasonically welding the release linerto the overlay or to the internal backing layer such as is described inthe U.S. patent application based on WO2009009651, which is incorporatedin its entirety herein as though fully set forth.

The overlay can also comprise a covering (1) that does not comprise aPSA, i.e., that comprises a non-PSA layer, such that the surface of theoverlay that is exposed to fingers, clothing and ambient dirt or dust isnon-tacky, is flexible or malleable so as to flex with skin and musclemovements, is of an unnoticeable or attractive color and texture, andpermits moisture from the skin to pass through the device owing to itsbeing porous or otherwise permeable to water.

Thus, it may be desirable to utilize a multi-layered overlay comprisinga first layer of a PSA in which the volatile component is insoluble,covered with an intermediate layer and an overlay covering having theproperties described above. Such illustrative overlay is illustrated inFIG. 1 as Layers 1, 2, and 3.

While a PIB PSA is useful for containing DMSO or ethyl lactate, or both,in the AI layer, the PIB PSA may flow through most overlay coveringshaving the properties described above. Such flow of the PIB PSA cancause the device to become tacky and discolored. Therefore, it may bedesirable to use an overlay covering that itself comprises two layers,one of which is a polymeric layer interposed between the PIB PSA (anintermediate layer) and a backing layer. Such intermediate layer can bea polyacrylate PSA as described above, because such PSA willsubstantially prevent flow of the PIB PSA into and through the overlaycovering but will substantially not itself migrate into or through theoverlay covering.

Thus, in an illustrative embodiment of the invention, the AI layercomprises a polyacrylate matrix further comprising a humectant, e.g.,PVP/VA, and skin permeation enhancers including DMSO, ethyl lactate, orboth, or another one or more volatile organic solvents; the overlay is alaminate that comprises three layers: a PIB PSA layer (3, in FIG. 1); anintermediate layer that comprises a material that does not permit flowof the PIB PSA but that does permit passage of moisture (2, in FIG. 1);and an overlay covering (or backing layer) that is non-tacky,attractive, flexible, and moisture permeable (1, in FIG. 1).

Materials useful in the intermediate layer include, e.g., polyacrylates,polyurethanes, plasticized polyvinyl chlorides, and copolymers ofpolyethylene and ethyl vinyl acetate. Rubber-based polymers that are ofvery high molecular weight, e.g., at least about 150,000 Daltons canalso be used, as can rubber-based polymers that can be crosslinked.Examples include the Kraton D styrene/butadiene, Kraton Gstyrene-ethylene/butylene-styrene or styrene-ethylene/propylene-styreneand Kraton IR linear polyisoprene homopolymers Butyl rubbers andsilicone rubbers, which are cross-linkable, can also be used. Theintermediate layer can comprise a PSA that binds the first overlay layeras well as the overlay covering. High molecular weight, cross-linkedpolymers are preferred. Preferably, such PSA is a polyacrylate such asis described above with reference to the AI layer.

Materials used in the overlay covering are not PSAs. They include, forexample, a polyurethane film, foam or spun bonded structure, apolyolefin foam, a PVC foam or a woven or non-woven fabric. Illustrativewovens include KOB 051, 053 and 055 woven polyesters (Karl Otto Braun.)Illustrative non-woven fabrics include polyesters. An illustrativepolyurethane material is CoTran™ 9700 melt-blown polyurethane nonwovenbacking (3M), which can be colored in skin tones. Suitable materials aredescribed, e.g., as backing layers in U.S. Pat. No. 6,660,295.

If the overlay covering is not porous, then it can be used without anintermediate layer. However, if the overlay covering is not porous,adhesion problems can result from a build up of moisture in the skin/PIBPSA interface. Use of a solid material, i.e., one that is not porous,but that is otherwise permeable to water, such as a thin, e.g., 1 mil(i.e., 0.001 inch), polyurethane film, can be used. However, a porousmaterial such as a foam or fabric will, in general, better retain itsshape and provide good adhesion.

Thus, based on the above description of an integrated transdermaldelivery system, it can be seen that an aspect of this embodiment of theinvention pertains to containing a volatile component in the AI layer byforming a seal between an overlay and a release liner.

Another aspect of this embodiment of the invention pertains to use of aPIB PSA in an overlay for an AI layer that comprises a volatile solvent,especially, DMSO, because DMSO is poorly soluble in PIB PSAs. See Table1, below, which compares the solubility of DMSO in a polyacrylate PSA(Duro Tak 87-4098, National Starch) and in a PIB PSA such as isdescribed above.

TABLE 1 SATURATION SOLUBILITIES (MG/G) PSA DMSO Ethyl Lactate LaurylLactate Duro-Tak 87-4098 8 150 1000 PIB PSA 0.01 0.03 785

These data indicate that DMSO and ethyl lactate, which are bothvolatile, cannot migrate into the PIB PSA because of saturationconsiderations. Of course, it will be understood that some amount ofabsorption into the overlay is acceptable and, indeed, unavoidable, atleast under certain conditions. It is important, however, in thisembodiment of the invention, that the solubility of the volatilecomponent in the AI containing layer be higher than, preferablysubstantially higher than, the solubility of the volatile component inthe overlay PSA. References herein to a PSA that does not absorbvolatile components must be understood in this context. In any event,the above data also indicate that the lauryl lactate, which isrelatively not volatile, can flow into the PIB PSA by contact, which iswhy an internal backing layer is preferred in the transdermal drugdelivery system of the invention.

Consistent with the above data, wear studies have shown that the PIB PSAretains its adhesiveness better than the polyacrylate PSA when stored inthe presence of volatile enhancers owing to the reduced tendency of thevolatile enhancers to migrate into the PIB PSA from an acrylic adhesiveAI matrix, which migration would adversely affect the PIB PSAadhesiveness.

Overlay PIB and polyacrylate PSAs were tested in wear studies todetermine their ability to adhere to skin for long periods of time.Table 2 shows that when absorption of excipients was minimized (25 Cexposure) the acrylic adhesive gave better results than the PIB. Whenabsorption of excipients was allowed to proceed in a more rapid rate (40C exposure) the adhesion provided by the PIB PSA was better than that ofthe acrylic PSA. It is important to note that the adhesivity of the PIBPSA was the same when exposed to higher (40 C) or lower (25 C)conditions, for absorption of volatile excipients.

TABLE 2 ADHESIVITY OF INTEGRAL OVERLAY/ACTIVE PATCHES OverlayEquilibration Equilibration Adhesive Time Temperature Adhesivity (1)Acrylic 1 month 25 C. 16.2 Acrylic 1 month 40 C. 12.8 PIB 1 month 25 C.15.1 PIB 1 month 40 C. 15.1 (1) Note: These are relative values in whicha higher number signifies better adhesion.

Another aspect of this embodiment of the invention pertains to use of anoverlay covering to cover the PIB PSA, which layer protects againstcontact with the PIB PSA and allows water vapor transmission. Anotheraspect of this embodiment of the invention pertains to use of a porousoverlay covering and an intermediate layer that is permeable to moisturebut that inhibits or prevents flow of the PIB PSA into and through theoverlay covering.

The data in Table 3, below, illustrate that (1) use of a urethaneoverlay with or without a PIB PSA layer (PIB PSA is protecting theurethane on one side only) will result in absorption, and thereforeloss, of volatile components such as are in the skin permeation enhancercomposition illustrated in Examples 1 and 2 and (2) a polyester filmdoes not absorb such components, even when coated with a PIB PSA such aswhen the internal backing layer is Mylar® and the overlay comprises aPIB PSA.

TABLE 3 ABSORPTION OF ENHANCERS BY PATCH COMPONENTS (wt %) 1.Polyurethane spun bonded CoTran(TM) 9700 (3M) 10.6 nonwoven for overlay2. Same as 1 but coated with Hi-Tack Nonwoven 9.65 acrylic adhesiveMedical Tape 9904 (3M) 3. Same as 2 but overcoated 7.6 with 2 mm of PIBPSA (similar to Table 1) Polyester internal backing layer Mylar ® 0.96Polyester coated with 2 mm PIB Mylar ® 1.12 PSA (similar to Table 1)

The data in Table 3 were obtained by placing in a metal dessicator the 4enhancers in the same ratio as in the patch described in the Examples,below. The different components of the patch were placed in the samedessicator, making certain that the liquid enhancers (which were placedin a beaker on the bottom of the dessicator) were not in contact withthe patch components. Therefore, any absorption of the enhancers intothe patch components could only take place through vapor transfer. Thedessicator was placed in a 40 C oven and the absorption into the patchcomponents was measured by weighing the samples and determining theweight gain after 3 months.

Polyester non-woven fabrics, e.g., KOB 053 and KOB 055, were also shownnot to absorb the volatile components to a significant extent.

EXAMPLES

The following examples are set forth to describe this embodiment of theinvention in greater detail. They are intended to illustrate, not tolimit, the invention.

Example 1 Fabrication of Transdermal Drug Delivery System

Example 1 is a description of one of the ways to fabricate a dermaldelivery system of the invention. It will be appreciated that other wayscan also be used. In this example, Part A illustrates preparation ofInternal Backing/AI layer/Release Liner Laminate. Part B illustratesfabrication of a foam/acrylic PSA/PIB PSA overlay structure. Part Cillustrates fabrication of an integrated device, or system, of theinvention utilizing the laminates prepared in Parts A and B.

Part A. Fabrication of an Internal Backing/AT layer/Release LinerLaminate: After deaeration, an adhesive polymer composition comprisingthe AI and the volatile component(s) is applied to the backing layermaterial, and subsequently dried for a set time at a set temperature. Inan alternative embodiment, the adhesive polymer matrix may be applied toa release liner instead of to the backing layer. Accordingly, referenceherein to application of the adhesive polymer matrix to the backinglayer will be understood to include this alternative embodiment.Application of the deaerated adhesive polymer matrix to the backinglayer may be accomplished using commercially available laboratorycoating/drying apparatus routinely used for this purpose. For instance,the Werner Mathis Model LTSV/LTH apparatus may be utilized, as well asother laboratory coating devices available from Werner Mathis AG(Zurich, Switzerland). Other suitable devices include, but are notlimited to, instruments produced by Chemsultants, Inc. (Mentor, Ohio).

The thickness of the adhesive polymer solution applied to the backinglayer, as well as the time and temperature of drying, are all processparameters that can be varied to achieve the final concentrations andratios of hormones and permeation enhancing agents within the patch. Forinstance, it has been found that a change in the thickness of adhesivepolymer matrix applied to the backing layer (e.g., from 300 to 800 μm)can result in an overall greater retention of volatile skin permeationenhancers when the other two process parameters, drying time and dryingtemperature, are held constant. In contrast, changing the drying time,e.g., from 5 to 25 minutes, or the drying temperature, e.g., from 40-100C, can result in overall losses in retention of volatile skin permeationenhancers, to a greater or lesser degree depending on the enhancer.

Thus, it will be appreciated by those of skill in the art that, inaddition to selection of appropriate amounts of starting materials inthe adhesive polymer starting formulation, an appropriate combination of(1) initial thickness of the deaerated adhesive polymer solution spreadon the backing layer, (2) drying time and (3) drying temperature may beselected to achieve the final composition of skin permeation enhancersand AIs in the device.

The dried adhesive polymer matrix is next laminated with a piece ofrelease liner (such as Scotchpak® 1022 or 9744, 3M Co., St. Paul Minn.)(or backing layer, if the alternative embodiment is utilized),preferably of the same size to form a sheet of the transdermal hormonedelivery systems.

Part B. Fabrication of a Non-Woven/Acrylic PSA/PIB PSA Overlay Laminate:The Fabrication of the Overlay is Performed in Two Steps.

In the first step, a PET-silicone coated release liner is unwound and asolution of an acrylic adhesive Duro-Tak 87-2852 is coated on thesilicone side of the release liner. The web proceeds through heatedovens where the solvents are blown off and the release liner/solidacrylic PSA laminate is formed. The laminate proceeds toward a laminatorunit where the 3M 9700 spun bonded non-woven is unwound and the acrylicPSA and the 3M 9700 go through the heated laminator rolls where a threelayer laminate is formed (3m 9700/acrylic PSA/silicone release liner).

In the second step a PET-silicone coated release liner is unwound and asolution of a PIB PSA is coated on the silicone side of the releaseliner. The web proceeds through heated rolls where the solvents areblown off and the release liner/solid PIB PSA laminate is formed. Thelaminate proceeds toward a laminator unit where the 3M 9700/acrylicPSA/silicone release liner laminate is positioned. The 3M 9700 laminateis unwound, its release liner is removed and discarded and the rest ofthe laminate proceeds toward the heated laminator rolls where itcombines and gets laminated to the release liner/solid PIB PSA laminateto form the finished overlay composed of 3M 9700 spun bondednon-woven/acrylic PSA/PIB PSA/silicone release liner.

Part C. Fabrication of an Integrated Device of the Invention (DoubleDisc Conversion Process):

The conversion of a double disc, peripheral adhesive transdermaldelivery device is fabricated on a die cutting-laminating piece ofequipment typical for the industry. It has at least two payout stations,two die cutting stations, one lamination station, and three rewindstations. A roll of overlay laminate (Polyurethane, Polyacrylate PSA andPIB PSA) from Part B and a roll of release liner/active patch/internalbacking layer laminate from Part A are mounted onto the payout spindles.The active patch laminate is threaded through a die cutting stationwhere a partial or kiss cut is performed in the shape of the activepatch through the internal backing and AI layer, and not through therelease liner. The waste material around the patches is delaminated fromthe protective liner and wound onto a rewind spindle.

The overlay laminate is threaded through the conversion machine, therelease liner is removed and the exposed overlay adhesive-urethanebacking is laminated over the patch and onto the release liner from theactive patch laminate. The resultant laminate with the active patchsandwiched between the overlay and the release liner is die cut in ashape larger than the active patch and collected for the next processingstep. The resulting liner with holes cut out in the shape of theoverlay-patch is wound on a rewind spindle.

Example 2 Control of Loss of Volatile Components

A transdermal hormone delivery device was prepared comprising aninternal backing layer, an AI layer, and a release liner. The AI layercomprised, as a polymer matrix PSA: Duro Tak 87-4098; as a humectant:PVP/VA-S360; as skin permeation enhancers: dimethylsulfoxide (DMSO),lauryl lactate (Ceraphyl® 31), ethyl lactate, and capric acid; as theAI: levonorgestrel and ethinyl estradiol.

The device also comprised an overlay comprising a polyurethane spunbonded non-woven backing, which is able to absorb large amounts of thevolatile excipients, DMSO and ethyl lactate, an acrylic PSA coated ontothe polyurethane foam, and a PIB PSA coated on top of the acrylic PSA.The internal backing layer was composed of a Mylar polyester backingfilm onto which was coated an acrylic PSA containing the AI as well asthe volatile excipients, DMSO and ethyl lactate at 8 wt % and 1.7 wt %nominal concentrations, respectively, and a non-volatile excipient,lauryl lactate at 8.4 wt % nominal concentration. The release liner wasa Mylar polyester film coated with a fluoropolymer release coating. Thepatches were assembled so that the release liner was in direct contactwith the PIB PSA of the overlay, forming an in situ seal around theactive patch.

The devices were placed in a 25 C or 40 C oven. After 6 weeks and 12weeks, devices were removed from the oven and the active section of eachdevice was separated from the overlay. The amounts of DMSO, lauryllactate, and ethyl lactate in the active patch were determined using gaschromatography. (12 weeks exposure to 40 C is intended to simulate 18months exposure to room temperature (25 C)). The results are shown inTable 4.

TABLE 4 Amounts of DMSO, Ethyl Lactate, and Lauryl Lactate in the AIPatch DMSO Ethyl Lactate Lauryl Lactate Conditions (wt %) (wt %) (wt %) 6 wks, 40 C. 9.02 1.66 9.02 12 wks, 40 C. 8.98 1.57 9.20 12 wks, roomtemp 9.08 1.79 9.10

These results demonstrate that the seal between the overlay and therelease liner and the use of an overlay, internal backing layer, andrelease liner, are adequate to prevent loss of volatile components(DMSO, ethyl lactate) and a non-volatile component (lauryl lactate).

Dermal delivery devices of the invention can optionally be packaged fordistribution and sale to users. Standard packaging can be used or, ifdesired, packaging that exerts pressure on the in situ seal between therelease liner and the PSA of the overlay can be employed. The purposefor such packaging is to keep the release liner and overlay in contactwith each other and to minimize slippage or gapping that might occur,e.g., during transportation. Such packaging can comprise a closablepacket (e.g., a clamshell packet that is hinged to open but that can besnapped close) that when closed fits snugly around the perimeter of thedelivery device, thereby exerting a small amount of pressure on the insitu seal, but that is shaped so as not to squeeze the AI-containingpatch.

Example 3 Clinical Study

Devices of a type described in Example 2 were analyzed for adhesion andirritation in a clinical study. Placebo patches or patches containingactives were applied to the skin of women for pre-determined timeperiods, among which were (1) one week, (2) two monthly treatmentcycles, and (3) three monthly treatment cycles.

Adhesion Analyses:

-   A) Placebo patches applied for one week to 59 women: one out of 59    patches (1.7%) exhibited meaningful degree of detachment;-   B) Active patches applied for two treatment cycles to 38 women: 12    out of 149 patches (8.1%) exhibited meaningful degree of detachment;-   C) Placebo and active patches applied for three treatment cycles to    59 women: 13 out of 208 patches (6.3%) exhibited meaningful degree    of detachment;

The mean cumulative total adhesion score (calculated per FDA Guidance)was 0.9 with an upper limit of 1.38 (placebo patch, one week, 59 women).

Irritation Analyses:

-   A) Placebo patches applied for one week to 54 women: 0 out of 54    patches (0.0%) resulted in significant irritation and 1 out of 54    patches (1.9%) resulted in moderate irritation.-   B) Active patches applied for two treatment cycles to 38 women: 0    out of 143 patches (0.0%) resulted in significant irritation and 6    out of 143 patches (4.2%) resulted in moderate irritation.-   C) Placebo and active patches applied for two treatment cycles to 54    women: 0 out of 197 patches (0.0%) resulted in significant    irritation and 7 out of 197 patches (3.6%) resulted in moderate    irritation.

The mean cumulative total irritation score (calculated per FDA Guidance)was 0.11 with an upper limit of 0.21 (placebo patch, one week, 54women).

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification withinthe scope of the appended claims. Published patent applications andpatents referenced in this specification are incorporated herein byreference as though fully set forth.

The invention claimed is:
 1. A non-heat sealed transdermal drug deliverydevice that comprises: (a) a polymer matrix active ingredient (AI) layerhaving a skin-contacting surface and a non-skin contacting surface; theAI layer comprising an active ingredient, a pressure sensitive adhesive(PSA), and at least one volatile component which is at least partlysolubilized in the PSA of the AI layer; (b) a release liner in directcontact with the skin-contacting surface of the AI layer, the perimeterof which extends beyond the perimeter of the AI layer in all directions;(c) an overlay adjacent to the non-skin contacting surface of the AIlayer, the perimeter of which extends beyond the perimeter of the AIlayer in all directions; the overlay comprising: (i) a PSA layer; and(ii) an overlay covering; and (d) an internal backing layer between theAI layer and the overlay; in which device: the PSA of the Al layer is apolyacrylate PSA; the volatile component comprises DMSO, ethyl lactate,or both; the PSA layer of the overlay is a polyisobutylene (PIB) PSA, asilicone PSA, a styrene/butadiene/styrene PSA, styrene/isoprene/styrenePSA, a styrene-ethylcne /butylene-styrene PSA, a styrene/butadiene PSA,a styrene-ethylene/butylene-styrene PSA, astyrene-ethylene/propylene-styrene PSA or an isoprene rubber PSA; therelease liner and the PSA layer of the overlay are in direct contactwith and adhered to each other around the perimeter of the Al layer toform a PSA seal between the overlay and the release liner; thesolubility of the volatile component in the PSA of the PSA layer of theoverlay is less than the solubility of the volatile component in the PSAof the AI layer such that the PSA seal between the overlay and therelease liner reduces or prevents loss of the at least one volatilecomponent from the Al layer; and the overlay covering is non-tacky,flexible, and moisture permeable; whereby at the end of an extended wearperiod, the patch causes cumulative moderate irritation plus significantirritation of less than 5% or exhibits meaningful degree of detachmentover a seven day wear period of less than 20%, or both.
 2. The device ofclaim 1, wherein the polyacrylate PSA of the AI layer is a polyacrylateadhesive copolymer having a 2-ethylhexyl acrylate monomer and 50 to 60wt% vinyl acetate as co-monomer.
 3. The device of claim 1, wherein therelease liner comprises a fluorinated or siliconized polymer film, or afoil lined with a siliconized or fluorinated polymer.
 4. The device ofclaim 1, wherein the PSA layer of the overlay comprises a silicone PSA.5. The device of claim 1, wherein the PSA layer of the overlay comprisesa PIB PSA and in which the overlay further comprises a polymericintermediate layer comprising a polyacrylate PSA.